Co-resistance to all first-line antibiotics necessitates the use of less effective or relatively toxic reserve antibiotics. Gram-negative bloodstream infections (GNBSI) harboring such difficult-to-treat resistance (DTR) may have worse outcomes than traditional resistance phenotypes that often retain susceptibility to 1 first-line agent. To more fully describe trends in difficult to treat resistance, we used a large de-identifed database from 173 hospitals with linked microbiologic, clinical, and demographic information (PremierTM) to describe DTR encounter characteristics. Inpatient encounters with select taxa of GNBSI were analyzed. Prevalence, aminoglycoside resistance and reserve agent use for DTR (intermediate/resistant in vitro to all carbapenems, -lactams and quinolones) were compared to three CDC-defined phenotypes (carbapenem-resistant CR, extended-spectrum cephalosporin-resistant ECR and fluoroquinolone-resistant FQR) and predictors of DTR were identified. Adjusted relative risk of mortality (aRR; Poisson regression) was examined for: (1) DTR: 2) CDC-defined phenotypes susceptible to 1 first-line agent; and (3) across diminishing active categories of first-line agents. Between 2009-2013, 471 (1%) of 45,011 GNBSI episodes at 90/173 hospitals exhibited DTR, ranging from 0.04% for E coli to 18.4% for A. baumannii. Among DTR cases, 79% received parenteral aminoglycosides, tigecycline, or colistin/polymixin-B, but 33% were resistant to all aminoglycosides. DTR was predicted by urban healthcare exposure and increased baseline illness. Crude mortality in DTR-GNBSI was 43%; aRR was higher for DTR- vs. CR- (aRR=1.2, 95% CI=1.0-1.4; p=0.02), ECR- (aRR=1.2, 1.1-1.4; p=0.001), or FQR- (aRR=1.2, 1.0-1.4; p=0.008) GNBSIs. Across CDC-defined phenotypes, aRR was similar (p>0.1 for all), but increased by 20% per drop in active first-line categories from at least 3 to 1 or 2 to zero. Non-susceptibility to first-line treatment options decreases survival in GNBSIs. DTR is a simple bedside measure of treatment-limiting co-resistance.